With the progress of intensive care for newborns made in recent years, the survival rate of infants with very low birth weight of 1,000 g or less has increased, while at the same time, due to exposure to high concentration oxygen applied during intensive cares, the incidence of retinopathy of prematurity (hereinafter may be simply referred to as “ROP”) has also increased. ROP is a major blinding disease occurring in premature infants who have been exposed to high concentration oxygen. The number of patients of such disease is as large as 30,000 per year within Japan only and is constantly increasing.
Neovascularization in the retina, which is a primary pathological change caused due to ROP, is related with local ischemia and subsequent development of abnormal neovascularization. It has been known that ROP involves serious deuteropathy such as blindness that may occur due to detachment of the retina. However, a factor that regulates the occurrence of ROP has not been clarified yet. No prophylactic treatments such as control of organs to be subjected to the load from oxygenation, use of antioxidants, in particular, use of vitamin E, has been successful so far.
With respect to the therapeutic method, it has been shown that coagulation of avascular retina with laser beam and a freezing treatment of avascular retina are partially effective for prophylaxis of blindness occurring in patients of ROP (e.g., Non-Patent Document 1).
Agents effective for therapy or prophylaxis of ROP have been proposed in consideration of neovascularization. Examples of such agents include: a composition including a combination of a specific sialyloligosaccharide (e.g., Patent Document 1), an insulin-like growth factor I (IGF-1) or an analog thereof, and an insulin-like growth factor-binding protein or an analog thereof (e.g., Patent Document 2); nitrate; nitrite (e.g., Patent Document 3) and the like.
On the other hand, a mastocyte (hereinafter may also be referred to as a “mast cell”) has a large number of granules inside the cell, and inside each granule, various substances known as chemotransmitters (chemical mediators) are included, such as histamine, serotonin, leukotriene, and heparin. When the mast cell is stimulated and thus activated (degranulated), these substances are released out of the cell. In this action, neovascularization is induced due to stimulation of proliferation of vascular endothelial cells applied by histamine and heparin stored in the mast cells.
In addition, it has been known that proteases such as tryptase or chymase released from a mast cell and cytokine such as tumor necrosis factor-α (TNF-α), interleukin-8, and a nerve growth factor are involved in normal neovascularization or neovascularization related to tumors (see Non-Patent Documents 2 to 5, for example).